18.03.17 Mitochondrial inheritance Flashcards
What are some of the functional properties of mitochondria?
- Sub-cellular double-membrane organelles responsible for producing cellular energy in the form of ATP via the oxidative phosphorylation pathway (OXPHOS).
- Location for important biochemical pathways: tricarboxylic acid (TCA) cycle, and parts of urea cycle.
- Regulation of apoptosis, cytosolic Ca concentration and Fe-S cluster biogenesis.
What are the properties of mtDNA, inc. size, no. genes etc.
16.6kb circular dsDNA molecule
encoding for 37 genes:
How many copies of the mt genome are present in each cell?
Each cell can contain up to several thousand copies of the mt genome (depends on energy demand of tissues).
Which genes do mtDNA encode for?
13 polypeptides of the OXPHOS system,
2 ribosomal RNAs
22 tRNAs (see Fig. 2).
Describe some of the properties of mt genes, including relative mutation frequency and inheritance.
- No introns, very few non-coding bases, termination codons are created post-transcriptionally by polyadenylation.
- Higher mutation frequency (~10x) than nDNA (close proximity of the mtDNA mutations to OXPHOS on inner mt membrane = increased susceptibility to damage through leakage of reactive oxygen species).
- MtDNA is almost exclusively transmitted through the maternal line.
What is meant by the terms heteroplasmy and homoplasmy?
The mtDNA can all be identical (homoplasmy). Alternatively there can be a mixture of two or more mt genotypes (heteroplasmy).
In these cases there is typically a threshold level where the mutation becomes clinically significant i.e. 50-60% for deleted mtDNA molecules; >90% point mutations in tRNA. However, a threshold level of <25% was detected in an individual affected with m.5545C→T (Sacconi et al., 2008).
Which three major classes of disease does mt dysfunction play a role in?
- Primary mt disease
- Neurodegeneration
- Cancer
As well as contributing to the decline in tissue integrity with age.
Give a brief overview of mt disease.
- Incidence <1/6500
- ~1 in 200 asymptomatic carriers
- Clinically heterogeneous group of disorders which arise as a result of dysfunction of the mt respiratory chain
What is the cellular effect of dysfucntion of the mt respiratory chain?
If a cell cannot produce enough ATP via OXPHOS, they may shunt pyruvate to lactate causing systemic lactic acidosis
Describe the clinical manifestations of mitochondrial disease, including age of onset.
Often unobserved; some disease causing mutations affect all copies of the mt genome (homoplasmic mutation); others only present in a proportion of mt (heteroplasmic mutation).
Many involve multiple organ systems and frequently effect tissues with high metabolic demand e.g. nervous system, skeletal muscle or heart (Fig. 4).
Other tissues include β-cells of pancreas (diabetes); inner hair cells of cochlea (deafness); renal tubules (kidney dysfunction).
Some only affect a single organ (e.g. the eye in LHON, see table below).
May present at any age, recent advances have shown that many mtDNA disorders present in childhood, while many nuclear genetic mt disorders present in adult life.
Give two examples of primary mitochondrial disease caused by deletions in the mt genome.
All three have several deleted genes, are heteroplasmic and are usually sporadic.
- Pearson syndrome: pancytopoenia, anaemia, lactic acidosis, pancreatic failure, infancy onset.
- Kearns-Sayre syndrome: progressive myopathy, deafness, opthalmoplegia, cardiomyopathy, adult onset
- CPEO (chronic progressive external opthalmoplegia) Opthalmoplegia, ptosis, impaired eye movement
Give three examples of primary mitochondrial disease caused by maternally-inherited heteroplasmic (only) point mutations in the mt genome.
- MELAS (Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes) point mutations in MT-TL1
- MERRF (Myoclonic epilepsy and ragged-red fibres) - ME, myopathy, cerebellar ataxia. PM in MT-TK.
- NARP (Neurogenic weakness, ataxia and retinitis pigmentosa) sensory neuropathy, ataxia, RP. PM in MT-ATP6
- MIDD (Maternally-inherited diabetes and deafness): Diabetes, deafness. PM in MT-TL1
What is an example of a disease caused by sporadic heteroplasmic point mutations in the mt genome?
Leigh/Leigh like: Encephalopathy, lactic acidosis. PM in MT-ATP6.
Which two diseases are caused by maternally-inherited heteroplasmic or homoplasmic point mutations in the mt genome?
- AID (aminoglycide-induced deafness: deafness. PM in MT-RNR1
- LHON (Leber hereditary optic neuropathy): Sub-acute bilateral visual failure and optic atrophy. Point mutations in MT-ND1, MT-ND4, MT-ND6.
> 1200 proteins in the mt are encoded by nDNA genes, in which defects can affect mtDNA maintenance and expression leading to mtDNA depeletion and multiple deletions. Give examples.
- POLG, POLG2, PEO1 - all have direct effects
- Indirect effects include disruption of nucleoside transport, salvage and synthesis e.g. SLC25A4 (encodes ANT the ATP/ADP translocator) and RRM2B- Since mtDNA continually replicates independently of nDNA, it requires a continual supply of dNTP’s. In mitotically active tissue, these are largely provided by import from the cytoplasm. However, in post-mitotic tissue, the mt is dependent on the salvage pathway again resulting in tissue specific phenotypes.